Analysis of gene expression in Tgif mutant mouse colon tumors.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE116578 | GEO | 2019/04/10
REPOSITORIES: GEO
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Project description:In this study, we analyzed global gene expressions of colon tumors from DNA hypomethylated and the control mice. We found that DNA hypomethylated tumors express significantly higher levels of intestinal differentiation-related genes when compared with the control tumors. These results suggest that DNA methylation may play a role in the maintenance of undifferentiated state of colon tumor cells. Two different Dnmt1 mutant alleles were used in this study; hypomorphic Dnmt1chip allele and conventional KO Dnmt1c allele, which described previously. Previous studies indicated that Dnmt1chip/c mice have reduced DNA methylation contents at pericentromeric satellite repeats, while Dnmt1chip/+ mice have the same levels of genomic methylation as wildtype mice. Experimental mice in an isogenic F1 hybrid background were obtained by breeding Dnmt1c/+; ApcMin/+ mouse in the C57BL/6 background with Dnmt1chip/chip; Apc+/+ mouse in the 129Sv4 background. Six-week-old DNA hypomethylated (Dnmt1chip/c; ApcMin/+) and the control (Dnmt1chip/+; ApcMin/+) mice were fed with 2% (w/v) dextran sodium sulfate (DSS), a potent promoter for colon carcinogenesis. At 20 weeks of age, colon tumors were harvested from both cohorts (n=3 for both DNA hypomethylated tumors and the control tumors) and analyzed for their gene expressions.
2015-08-05 | E-GEOD-60620 | biostudies-arrayexpress
Project description:Adenomatous polyposis coli (APC) is an important tumor suppressor and most directly related to the regulation of WNT/β-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). However, obvious prognostic differences are observed in CRC patients with APC mutations. Although previous genomics has investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. By using combined proteome and phosphoproteome, we classified the APC-mutant colon cancer patients and revealed the genomic, proteomic and phosphoproteomic heterogeneity in APC-mutant tumors. Of importance, we identified RAI14 as a key prognostic determinant for APC-mutant colon cancer patients, but not for APC-wildtype colon cancer patients. The heterogeneity and prognostic biomarkers in APC-mutant tumors were further confirmed in Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that knockdown of RAI14 in cell lines led to reduced cell migration and changes in some epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, knockdown of RAI14 was able to remodel the phosphoproteome associated with cell adhesion, which might promote F-action degradation and alter the expression of certain EMT markers. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies the prognostic determinants for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment.
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Project description:The first step in the development of human colorectal cancer (CRC) is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (APC) gene which encodes an essential tumor suppressor. In order to identify genes affected by Apc loss, expression profiling of intestinal epithelium isolated from mice harboring the conditional allele of the gene was performed. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. To characterize the gene signature in colon upon Msx1 depletion, colonic epithelium from mice harboring conditional alleles of Apc and Msx1 was isolated and the gene expression profile was compared with control mice harboring the conditional allele of Apc only.
2019-11-01 | E-MTAB-6909 | biostudies-arrayexpress
Project description:We tamoxifen treated 8-12 week old mice that had floxed alleles of the following: 1) both Apc alleles (giving rise to Apc truncation/inactivation); 2) both Cdx2 alleles (giving rise to Cdx2 inactivation; 3) one Braf allele, that upon Cre-mediated recombination gives a Braf V600E mutant allele (details below), and 4) the combination of both the Cdx2 alleles and the BrafV600E allele. All four of those groups also had a CDX2P-CreERT2 transgene that expresses Cre recombinase fused to a tamoxifen-regulated fragment of the estrogen receptor ligand binding domain. CreERT2 expression occurs only in tissues where the Cdx2 gene is expressed, which is almost exclusively in adult mouse cecum and colon epithelium. A fifth group of mice had the floxed Cdx2 alleles, but no CDX2P-CreERT2 gene. Treating the mice having CDX2P-CreERT2 with tamoxifen permits the Cre recombinase to enter the cell nucleus and recombine the Apc, Braf, and/or Cdx2 alleles containing loxP sequence elements. Mice were treated with intraperitoneal injection of tamoxifen dissolved in corn oil. Three mice per group were used. The control mice did not develop tumors or any morphological or histological changes in their epithelium, but their colons were used to create the 3 control samples. To obtain the BrafV600E allele we used a genetically engineered mouse line previously described by Dankort et al. (Genes Dev 2007, 21:379-84) that can express the BrafV600E mutant protein following Cre-mediated recombination. The Braf(CA) (Braf-Cre-activated) allele mice carry a gene-targeted allele of Braf, where Braf sequences from exons 15-18 are present in the normal mouse Braf intron 14, followed by a mutated exon 15 (carrying the V600E mutation). The exon 15-18 sequence element is flanked by loxP sites. In the absence of Cre-mediated recombination, the Braf(CA) allele expresses a wild type Braf protein. Following Cre-mediated recombination, the Braf exon 15-18 element is removed, and the Braf(CA) allele then encodes the Braf V600E protein (from the introduced mutated exon 15). RNA was purified from tumor or normal tissue, and targets for Affymetrix arrays were synthesized from the mRNAs. We used Affymetrix Mouse Gene 2.1 ST arrays, which hold 41345 probe-sets, but we largely analyzed just those 25216 probe-sets that were mapped to Entrez gene IDs. Raw data was processed with the Robust Multi-array Average algorithm (RMA). Data is log2-transformed transcript abundance estimates. We fit a one-way ANOVA model to the five groups of samples. We supply a supplementary excel workbook that holds the same data as the data matrix file, but also holds the probe-set annotation at the time we analyzed the data, and some simple statistical calculations, which selects subsets of the probe-sets as differentially expressed between pairs of groups, as well as significant Cdx2-/- by Braf V600E interactions. It also gives the homologous human gene IDs we used for enrichment testing, which were 1-to-1 best homologs according to build 68 of NCBI's Homologene. A second supplementary sheet shows the data we enrichment tested after collapsing to distinct human homologs, joins of the results of tests with GSE4045 data and of tests with TCGA data to the mouse genes, and the intersections of selected genes in those data set with our gene selections in mouse. Consumers should consider obtaining more up-to-date probe-set annotation for the array platform.
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Project description:A collection of genetically engineered mouse models (GEMM) of colorectal cancer (CRC) were created, and primary tumors from these GEMMs were analyzed. Primary CRC tumors from these GEMMs were genotyped to confirm that they contain the core genetic lesions of interest, including APC, P53, KRAS, and BRAF. Primary tumors from GEMMs with combinations of lesions of interest were analyzed by whole genome expression, and their expression profiles were compared to determine how they segregate. Signatures were then generated from GEMM tumors of interest and compared to human clinical datasets with expression and outcome data. Primary tumors from CRC GEMMs with different combinations of mutant alleles of interested were generated and analyzed. Alleles include mutant forms of APC (A), P53 (P), KRAS (K) and BRAF (B).
2014-07-01 | E-GEOD-50794 | biostudies-arrayexpress
Project description:Members of the TALE (Three-amino acid loop extension) family of atypical homeodomain-containing transcription factors are prominent downstream effectors of oncogenic fusion proteins generated from translocations involving the mixed lineage leukemia (MLL) gene. A particular well-characterized member of this protein family is MEIS1, which together with HOXA proteins, orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). Although TALE family proteins are mainly described as transcriptional activators TGIF1 (TGF-β induced factor) / TGIF2 are considered as transcriptional repressors. However, as their function in MLL-rearranged AML is largely unknown, we tested the potential importance of TGIF1 in the maintenance of MLL-rearranged AML. We find that expression of TGIF1 in MLL-AF9 transformed cells (MAF9) leads to cell cycle exit and differentiation in vitro and delayed leukemic onset in vivo. In accordance, MLL-rearranged patient blasts display lower levels of TGIF1 and TGIF1 expression in general correlates positively with survival. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating to MEIS1-bound region in a competitive manner. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for the maintenance of MLL-rearranged AML.
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Project description:The aim of the study was to investigate the role of TGIF1 in MLL-AF9 transformed cells Members of the TALE (Three-amino acid loop extension) family of atypical homeodomain-containing transcription factors are prominent downstream effectors of oncogenic fusion proteins generated from translocations involving the mixed lineage leukemia (MLL) gene. A particular well-characterized member of this protein family is MEIS1, which together with HOXA proteins, orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). Although TALE family proteins are mainly described as transcriptional activators TGIF1 (TGF-β induced factor) / TGIF2 are considered as transcriptional repressors. However, as their function in MLL-rearranged AML is largely unknown, we tested the potential importance of TGIF1 in the maintenance of MLL-rearranged AML. We find that expression of TGIF1 in MLL-AF9 transformed cells (MAF9) leads to cell cycle exit and differentiation in vitro and delayed leukemic onset in vivo. In accordance, MLL-rearranged patient blasts display lower levels of TGIF1 and TGIF1 expression in general correlates positively with survival. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating to MEIS1-bound region in a competitive manner. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for the maintenance of MLL-rearranged AML.
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